The goal of this NRSA F30 award is to provide support for my M.D./Ph.D. training at Tufts University School of Medicine. This comprehensive training plan, which includes coursework and other educational activities along with the proposed research, is designed to facilitate my pursuit of a successful career as a clinician scientist. My proposed research falls into the field of osteoarthritis (OA), which is the most common joint disease in the United States. OA causes chronic pain and long-term disability in a large population of patients; however, the pathogenesis of OA is still not well understood. Dysfunctional chondrocyte matrix homeostasis has been pinpointed as an essential part of OA development. In OA, chondrocytes begin to secrete more matrix- degrading enzymes while decreasing their secretion of matrix proteins, thus accelerating cartilage matrix degradation. A better understanding of the signaling pathways that positively and negatively regulate cartilage matrix homeostasis in OA will lead to the development of therapeutics that can halt disease progression. Wnt signaling has been implicated in the regulation of cartilage matrix homeostasis in OA. Most published data suggests that Wnt exacerbates articular cartilage loss under OA conditions. However, conflicting results have been seen on downstream Wnt signaling components. As a result, the specific roles of Wnt signaling pathways in OA are still remain unclear. My preliminary data demonstrate that Wnt7a, which has the possibility of acting through both Wnt canonical and non-canonical pathways, promotes cartilage matrix preservation under OA conditions in vitro and in a surgical OA model in vivo. This result challenges the current view on Wnt in OA. Based on my study, I formed the central hypothesis that Wnt7a is a critical factor that promotes cartilage integrity under OA conditions. I plan to test this hypothesis by pursuing the following Specific Aims: 1. Investigate whether Wnt7a is sufficient to alter the course of cartilage matrix degradation and chondrocyte survival in in vivo OA mice. 2. Determine if Wnt7a is necessary for articular cartilage maintenance under OA conditions. 3. Identify the downstream Wnt pathway(s) that Wnt7a is activating under OA conditions. By performing this study, we will gain new knowledge on the signaling events that govern the homeostasis of articular cartilage, which will help provide a mechanistic framework to approach therapeutic strategies for OA. Thus, my work is significant from both a basic and translational science point of view. This proposed research activity will be coupled with opportunities to develop writing, communication and mentoring skills, including attending and presenting at scientific conferences, manuscript and grant writings, and supervising students or trainees in the laboratory. By carrying out these training activities, I will have a solid foundation to achieve my career goal of becoming an independently funded physician scientist.